Factors associated with quality of life in patients with kidney failure managed conservatively and with dialysis: a cross-sectional study.

BACKGROUND: Later stage chronic kidney disease (CKD) is associated with poorer self-perceived health-related quality of life (HRQOL), a major consideration for many patients. Psychological factors such as depression and anxiety have been linked with poorer HRQOL. We aimed to determine if anxiety or depressive symptoms are significantly associated with self-perceived health-related quality of life, in patients with CKD Stage 5. The secondary aim was to determine which patient-associated factors are associated with HRQOL in patients with CKD Stage 5. METHODS: This retrospective cross-sectional study included patients that attended the St George Hospital Kidney Supportive Care (KSC) clinic between 1 and 2015 and 30 June 2022 with CKD Stage 5 (either conservatively-managed or receiving dialysis). Patients completed surveys of their functional 'domains' and quality of life (EQ-5D-5L) and symptom surveys (IPOS-Renal) at their first visit. We performed multivariable linear regression analysis with the outcome of interest being HRQOL, measured using the EQ-VAS, a continuous 100-point scale, for patients undergoing conservative management or dialysis. Pre-specified variables included age, sex, eGFR (for those conservatively-managed), "feeling depressed" (IPOS-Renal), "feeling anxious" (IPOS-Renal) and "anxiety/depression" (EQ-5D-5L). RESULTS: We included 339 patients. 216 patients received conservative kidney management (CKM) and 123 patients received dialysis. Patients receiving CKM were significantly older than those on dialysis, (median age 83 years vs. 73 years, p < 0.001). For conservatively-managed patients, variables independently associated with poorer EQ-VAS were difficulty performing usual activities (EQ-5D-5L), drowsiness (IPOS-Renal) and shortness of breath (IPOS-Renal). For patients receiving dialysis, variables that were independently associated with poorer EQ-VAS were reduced ability to perform self-care (EQ-5D-5L) and lack of energy (IPOS-Renal). Anxiety and depressive symptoms were not significantly associated with poorer EQ-VAS for either group of patients. CONCLUSIONS: Symptoms associated with reduced HRQOL include shortness of breath, drowsiness and impaired functional ability. Optimization of multidisciplinary teams focusing on these issues are likely to be of benefit.

Quality of Life in Patients with Chronic Kidney Disease Managed with or without Dialysis: An Observational Study.

Background: Emerging research suggests that quality of life (QOL) outcomes, such as maintenance of independence, rather than length of life, are the main priority for many patients with end stage kidney disease (ESKD). There is therefore a need to focus on whether QOL for older patients on dialysis differs significantly from conservative kidney management (CKM). This study aimed to describe the QOL trajectory for patients with ESKD, comparing CKM to dialysis and transplantation. Methods: This retrospective, observational study included all patients who attended the Kidney Supportive Care Clinic at St. George Hospital and had one or more EuroQOL (EQ5D5L) questionnaires between July 2014 and May 2020. Kruskal-Wallis tests compared QOL scores between groups at baseline and 12 months. Wilcoxon signed rank tests compared QOL scores from baseline to 18 months within groups. Chi-squared tests compared proportions of patients reporting problems with QOL "domains" between the groups at baseline and 12 months. McNemar's tests compared changes in proportions of patients reporting problems with QOL "domains" within groups from baseline to 12 months. Results: A total of 604 patients had an initial survey. At baseline, patients who were managed conservatively reported more problems with mobility, self-care, and ability to perform usual activities. However, pain/discomfort and anxiety/depression were no higher in the conservative population. CKM patients reported no significant decline in mobility, self-care, ability to perform their usual activities, pain/discomfort, or anxiety/depression after 12 months or in QOL scores after 18 months compared with the other groups. Conclusions: QOL scores or symptom burdens did not change significantly in patients receiving CKM compared with dialysis, suggesting that appropriately supported CKM can maintain patients' QOL.

End-stage kidney disease: The last 12 months.

BACKGROUND: Chronic kidney disease (CKD) is increasingly prevalent in Australia's ageing population. Over the past decade, there has been growing recognition that dialysis does not benefit every patient with end-stage kidney disease (ESKD). Patients with advanced age, significant comorbidities and poor functional status may not gain a survival benefit with dialysis when compared with being managed conservatively. These developments have implications for general practitioners (GPs). A further development has been the emergence of renal supportive care, a patient-centred approach that integrates the principles of palliative care into nephrology. OBJECTIVE: The aim of this article is to outline salient aspects in the care of patients with ESKD. DISCUSSION: Salient aspects throughout the trajectory of ESKD are discussed, including symptoms of CKD, relevant management, prognostication, advance care planning discussions and end-of-life care. The role of the GP is vital, and it is recommended that GPs are involved early in a patient's CKD trajectory.

Factors Influencing Long-Term Patient and Allograft Outcomes in Elderly Kidney Transplant Recipients.

INTRODUCTION: Individuals aged ≥65 years are increasingly prevalent on the waitlist for kidney transplantation, yet evidence on recipient and donor factors that define optimal outcomes in elderly patients after kidney transplantation is scarce. METHODS: We used multivariable Cox regression modeling to determine the factors associated with all-cause death, death with a functioning graft, and overall and death-censored graft survival, using data from the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry. RESULTS: A total of 802 kidney transplant recipients aged ≥65 years underwent their first transplantation between June 2006 and December 2016. Median age at transplantation was 68 years (interquartile range = 66-69 years). The 1-year and 5-year overall patient and graft survivals (95% confidence interval [CI]) were 95.1 (93.5-96.7) and 79.0 (75.1-82.9), and 92.9 (91.1-94.7) and 75.4 (71.3-79.5), respectively. Factors associated with higher risks of all-cause death included prevalent coronary artery disease (adjusted hazard ratio [95% confidence interval] = 1.47 [1.03-2.11]), cerebrovascular disease (1.99 [1.26-3.16]), increasing graft ischemic time (1.06 per hour [1.03-1.09]), donor age (1.02 per year [1.01-1.03]), delayed graft function (1.64 [1.13-2.39]), and peritoneal dialysis pretransplantation (1.71 [1.17-2.51]). CONCLUSION: Prevalent vascular disease and peritoneal dialysis as a pretransplantation dialysis modality are risk factors associated with poorer outcomes in transplant recipients aged ≥65 years. Careful selection and evaluation of potential candidates may improve graft and patient outcomes in older patients.

Membrane transport status does not predict peritonitis risk in patients on peritoneal dialysis.

AIM: The aim of this study is to determine whether peritoneal membrane transport status (MTS) is associated with peritonitis or poor peritoneal dialysis-related outcomes. METHODS: This retrospective cohort study analysed data of incident adult patients on peritoneal dialysis in Western Sydney between 1 October 2003 and 31 December 2012. Only patients who underwent peritoneal equilibration and adequacy tests within 6 months of commencement were included. Kaplan-Meier survival curves for time until first peritonitis and time until composite endpoint of peritonitis, death or technique failure, censored for transplant, were constructed. RESULTS: About 397 patients, mean age 58.8(+/-2SD29) years, body mass index (BMI) 26.6(+/-5) kg/m2 and serum albumin 35.4(+/-5) g/L were included. About 59.2% had high/high-average peritoneal MTS; 45.8% were past and current smokers; 51.9% developed at least one episode of peritonitis; 7.6% changed to haemodialysis; 6.3% underwent transplantation; 8.8% died; and 25.4% remained free of the aforementioned events over a mean follow-up period of 22.5 months (range 0-115 months). Peritoneal MTS was not associated with time to first peritonitis (p = 0.67) or composite endpoint of peritonitis, death or technique failure (p = 0.12). Smoking and hypoalbuminaemia independently predicted time to first peritonitis. Past and current smokers had a hazard ratio of 1.38 (95% CI 1.03-1.86) for shorter time to first peritonitis, significant after adjustment for serum albumin (p = 0.033). Serum albumin <32 g/L had a hazard ratio of 1.74 (95% CI 1.13-2.67) for shorter time to first peritonitis, significant after adjusting for smoking (p = 0.012). CONCLUSION: Smoking and hypoalbuminaemia, but not MTS, were associated with shorter time to first peritonitis and composite endpoint of peritonitis, death and technique failure.

Roles of notch signalling in mandibular condylar cartilage.

IMPORTANCE: Notch proteins are cell surface transmembrane spanning receptors which mediate critically important cellular functions through direct cell-cell contact. Interactions between Notch receptors and their ligands regulate cell fate decisions such differentiation, proliferation and apoptosis in numerous tissues. We have previously shown using immunohistochemistry that Notch1 is localized primarily to the prechondroblastic (chondroprogenitor) layer of the mandibular condylar cartilage (MCC). OBJECTIVE: To test if Notch signalling changes patterns of proliferation and differentiation in the MCC and to investigate if Notch signalling acts downstream of Fibroblast Growth Factor 2 (FGF-2). METHODS: Condylar cartilage explants were cultured over serum-free DMEM containing either 0 or 50nM DAPT, a Notch signal inhibitor. Explants were used for RNA extraction and immunohistochemistry. RESULTS: Analysis of gene array data demonstrated that the perichondrial layer of the MCC is rich in Notch receptors (Notch 3 and 4) and Notch ligands (Jagged and Delta) as well as various downstream facilitators of Notch signalling. Disruption of Notch signalling in MCC explants decreased proliferation (Cyclin B1 expression) and increased chondrocyte differentiation (Sox9 expression). Moreover, we found that the actions of FGF-2 in MCC are mediated in part by Notch signalling. CONCLUSION: These data suggest that Notch signalling contributes to the regulation of proliferation and differentiation in the MCC.

A systematic review of the diagnostic performance of orthopedic physical examination tests of the hip.

BACKGROUND: Previous reviews of the diagnostic performances of physical tests of the hip in orthopedics have drawn limited conclusions because of the low to moderate quality of primary studies published in the literature. This systematic review aims to build on these reviews by assessing a broad range of hip pathologies, and employing a more selective approach to the inclusion of studies in order to accurately gauge diagnostic performance for the purposes of making recommendations for clinical practice and future research. It specifically identifies tests which demonstrate strong and moderate diagnostic performance. METHODS: A systematic search of Medline, Embase, Embase Classic and CINAHL was conducted to identify studies of hip tests. Our selection criteria included an analysis of internal and external validity. We reported diagnostic performance in terms of sensitivity, specificity, predictive values and likelihood ratios. Likelihood ratios were used to identify tests with strong and moderate diagnostic utility. RESULTS: Only a small proportion of tests reported in the literature have been assessed in methodologically valid primary studies. 16 studies were included in our review, producing 56 independent test-pathology combinations. Two tests demonstrated strong clinical utility, the patellar-pubic percussion test for excluding radiologically occult hip fractures (negative LR 0.05, 95% Confidence Interval [CI] 0.03-0.08) and the hip abduction sign for diagnosing sarcoglycanopathies in patients with known muscular dystrophies (positive LR 34.29, 95% CI 10.97-122.30). Fifteen tests demonstrated moderate diagnostic utility for diagnosing and/or excluding hip fractures, symptomatic osteoarthritis and loosening of components post-total hip arthroplasty. CONCLUSIONS: We have identified a number of tests demonstrating strong and moderate diagnostic performance. These findings must be viewed with caution as there are concerns over the methodological quality of the primary studies from which we have extracted our data. Future studies should recruit larger, representative populations and allow for the construction of complete 2×2 contingency tables.

Correlation between metal allergy and treatment outcomes after ankle fracture fixation.

PURPOSE: To determine correlation between metal hypersensitivity and long-term foot and ankle function and pain after internal fixation using stainless steel implants. METHODS: 60 men and 46 women (mean age, 47 years) who underwent internal fixation for ankle fractures completed a questionnaire 13 to 38 (mean, 26) months after surgery to assess their existing medical condition, history of metal hypersensitivity, problems and outcome of the implant (revision or removal), and the American Academy of Orthopaedic Surgeons (AAOS) foot and ankle score. A subset of 12 men and 15 women then underwent patch testing for metal hypersensitivity to molybdenum, chromium, iron, manganese, and nickel. Patients with positive and negative reactions were compared. RESULTS: 21 of the 106 patients underwent removal of the metal implants. The AAOS score was not associated with any of the variables, except for a history of metal hypersensitivity from dental implants and irritation around the surgical scar. Multiple linear regression analysis showed that only irritation around the surgical scar remained associated with poorer AAOS scores. Five of the 27 tested patients had a positive reaction. The mean AAOS scores did not differ significantly between patients with positive and negative reactions (34 vs. 31, p=0.73). Gender was not associated with the test results (p=0.63). None of the 5 patients with a positive reaction underwent revision surgery or reported any history of asthma or metal hypersensitivity. Of the 27 patients, one of the 8 who reported itching, irritation, redness or rash around the surgical scar had a positive reaction, compared to 4 of 19 patients who reported no such symptoms (p=1). Two of the 27 patients reported development of eczema after fixation, one of whom had a positive reaction. Only one of the 27 patients reported a history of metal hypersensitivity to jewellery, but had a negative reaction.. CONCLUSION: Neither a history of metal hypersensitivity nor positive patch testing correlated with poor outcomes after internal fixation for ankle fractures using stainless steel implants.

Cell fate mediators Notch and Twist in mouse mandibular condylar cartilage.

OBJECTIVE: The objectives of this study were to examine if Twist and Notch 1 are present in the mandibular condylar cartilage (MCC) and whether their gene expression can be altered by exogenous FGF-2 and TGF-ß2. DESIGN: Half-heads from CD-1 mice pups harvested at embryonic day 17 (E17) were fixed, decalcified, and sectioned in the sagittal plane for immunohistochemical detection of Notch and Twist using confocal microscopy. Other mandibular condyles and adjacent ramus from E17 mice were cultured in serum-free DMEM containing 0, 3, or 30 ng/mL of FGF-2 (10-12 condyles per treatment group). This experimental design was repeated with medium containing 0, 3, or 30 ng/mL of TGF-ß2. After 3 days of culture, the pooled RNA from each group was extracted for examination of Notch and Twist gene expression using quantitative real-time RT-PCR. RESULTS: Immunohistochemical examination revealed that Notch and Twist were localized to the prechondroblastic and upper chondroblastic layers of the cartilage. Exogenous FGF-2 up-regulated Notch 1, Twist 1 and Twist 2 gene expression in MCC explants from E17 mice, whilst TGF-ß2 had the opposite effect. CONCLUSIONS: The gene expression data demonstrate that MCC explants are sensitive to growth factors known to affect Notch and Twist in other tissues. The subset of cells in which Twist and Notch immunoreactivity was found is suggestive of a role for FGF-2 and TGF-ß2 as regulators of cell differentiation of the bipotent MCC cell population, consistent with the role of Notch and Twist as downstream mediators of these growth factors in other tissues.

Sclerostin is a direct target of osteoblast-specific transcription factor osterix.

Osterix (Osx) is an osteoblast-specific transcription factor required for osteoblast differentiation and bone formation. Osx knock-out mice lack bone completely. Recent findings that Osx inhibits Wnt signaling provide a feedback control mechanism involved in bone formation. Mechanisms of Osx inhibition on Wnt signaling are not fully understood. Our results in this study revealed that the expression of a Wnt antagonist Sclerostin (Sost) was downregulated in Osx-null calvaria. Overexpression of Osx in stable C2C12 mesenchymal cell line resulted in Sost upregulation. Transient transfection assay showed that Osx activated 1kb Sost promoter reporter activity in a dose-dependent manner. To define Sost promoter activated by Osx, we made a series of deletion mutants of Sost constructs, and narrowed down the minimal region to the proximal 260bp. Gel shift assay indicated that Osx bound to GC-rich site within this minimal region, and that point mutations of this binding site disrupted Osx binding. Moreover, the same point mutations in 260bp Sost promoter reporter disrupted the promoter activation by Osx, suggesting that the GC-rich binding site was responsible for Sost promoter activation by Osx. To further examine physical association of Osx with Sost promoter in vivo, Chromatin immunoprecipitation (ChIP) assays were performed using primary osteoblasts from mouse calvaria. Osx was found to associate with endogenous Sost promoter. Taken together, these findings support our hypothesis that Sost is a direct target of Osx. This provides a new additional mechanism through which Osx inhibits Wnt signaling during bone formation.

Erk1/2 signaling is required for Tgf-beta 2-induced suture closure.

Transforming growth factors beta (Tgf-betas) act by means of Smad signaling pathways and may also interact with the mitogen-activated protein kinase pathway. The hypothesis was tested that Erk1/2 signaling is required for Tgf-beta2-induced suture closure, by culturing embryonic mouse calvariae in the presence of Tgf-beta2 with or without Erk1/2 inhibitor PD98059 (PD). Suture widths were measured daily, and microdissected sutures and bones were homogenized and protein analyzed by Western blots. Tgf-beta2 induced narrowing of the sutures after 72 hr, an effect inhibited by treatment with PD. Erk1/2 and Egf but not Smad2/3 protein expression was up-regulated by Tgf-beta2 calvarial tissues at 72 hr. PD inhibited endogenous and Tgf-beta2-stimulated Erk1/2 protein as well as Tgf-beta2-stimulated Egf, but increased Smad2/3 protein expression. In tissues harvested 0, 15, and 30 min after exposure to Tgf-beta2, Erk1/2 phosphorylation was up-regulated after 15 min, an effect abrogated by the simultaneous addition of PD. In summary, Tgf-beta2 stimulated Erk1/2 phosphorylation and induced Egf and Erk1/2 expression, associated with suture closure after 72 hr. Blocking Erk1/2 activity with PD inhibited these effects but increased Smad2/3 expression. We postulate that Tgf-beta2 regulates suture closure directly by means of phosphorylation of Erk1/2 and indirectly by up-regulating Erk1/2, a substrate for Fgf receptor signaling required for Fgf induction of premature suture obliteration.